Hyperresponsivity to Low-Dose Endotoxin during Progression to Nonalcoholic Steatohepatitis Is Regulated by Leptin-Mediated Signaling

• Published in: Cell metabolism Vol. 16; no. 1; pp. 44 - 54
• Main Authors: Imajo, Kento, Fujita, Koji, Yoneda, Masato, Nozaki, Yuichi, Ogawa, Yuji, Shinohara, Yoshiyasu, Kato, Shingo, Mawatari, Hironori, Shibata, Wataru, Kitani, Hiroshi, Ikejima, Kenichi, Kirikoshi, Hiroyuki, Nakajima, Noriko, Saito, Satoru, Maeyama, Shiro, Watanabe, Sumio, Wada, Koichiro, Nakajima, Atsushi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.07.2012
• Subjects: Alanine Transaminase - blood; Animals; Cell Line; Cytokines - blood; Cytokines - genetics; Cytokines - metabolism; Diet, High-Fat - adverse effects; Fatty Liver - etiology; Fatty Liver - immunology; Fatty Liver - metabolism; Fatty Liver - pathology; Gene Expression; Hepatitis, Animal - etiology; Hepatitis, Animal - immunology; Hepatitis, Animal - metabolism; Hepatitis, Animal - pathology; Humans; Leptin - metabolism; Leptin - physiology; Lipopolysaccharide Receptors - genetics; Lipopolysaccharide Receptors - metabolism; Lipopolysaccharides - pharmacology; Liver Cirrhosis; Liver Cirrhosis, Experimental - etiology; Liver Cirrhosis, Experimental - immunology; Liver Cirrhosis, Experimental - metabolism; Liver Cirrhosis, Experimental - pathology; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Non-alcoholic Fatty Liver Disease; Signal Transduction; STAT3 Transcription Factor - metabolism; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - metabolism; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2012.05.012

Although bacterial endotoxin, such as lipopolysaccharide (LPS), plays a key role in the pathogenesis of nonalcoholic steatohepatitis (NASH), detailed mechanisms of this pathogenesis remain unclear. Here, we demonstrate that upregulation of CD14 by leptin-mediated signaling is critical to hyperreactivity against endotoxin during NASH progression. Upregulation of CD14 in Kupffer cells and hyperreactivity against low-dose LPS were observed in high-fat diet (HFD)-induced steatosis mice, but not chow-fed-control mice. Hyperresponsivity against low-dose LPS led to accelerated NASH progression, including liver inflammation and fibrosis. Administering leptin in chow-fed mice caused increased hepatic expression of CD14 via STAT3 signaling, resulting in hyperreactivity against low-dose LPS without steatosis. In contrast, a marked decrease in hepatic CD14 expression was observed in leptin-deficient ob/ob mice, despite severe steatosis. Our results indicate that obesity-induced leptin plays a crucial role in NASH progression via enhanced responsivity to endotoxin, and we propose a mechanism of bacteria-mediated progression of NASH. [Display omitted] ► HFD-induced steatosis in mice promotes hyperresponsivity to low-dose LPS► CD14-positive Kupffer cells induced by feeding HFD regulate responsivity to LPS ► Leptin regulates CD14 expression in Kupffer cells via STAT3 signaling ► Leptin plays a critical role in NASH via control of responsivity to endotoxin